Date of Award
Doctor of Philosophy (PhD)
Jason A. Burdick
Cartilage, the load-bearing, low-friction articulating surface in diarthrodial joints, has a very low regenerative capacity, and clinical methods for cartilage treatment are limited. The underlying goal of this thesis was to develop novel fibrous hyaluronic acid (HA)-based hydrogels with controlled, tunable material parameters and ultimately to apply these materials as acellular scaffolds in vivo for improved cartilage repair. To this end, HA was electrospun with optimized parameters to form fibrous hydrogels with a wide range of material properties and the ability to entrap, release, and retain activity of biological factors, such as transforming growth factor β3 (TGFβ3). These fibrous HA hydrogels were first investigated through in vitro cell studies with mesenchymal stem cells (MSCs). Generally, softer and less adhesive fibers resulted in enhanced chondrogenesis, with adhesive ligand concentration dominating cell spreading, focal adhesion formation, and the ability of cells to pull on fibers. Various methods were then explored to increase cell infiltration; however, cell infiltration into fibrous HA scaffolds was limited even with the most promising techniques, reducing their potential as in vitro-cultured cell scaffolds.
To investigate their utility as acellular scaffolds for cartilage repair, fibrous HA hydrogels were implanted after microfracture in porcine cartilage defects. Scaffold groups included those with or without a degradable HA fiber component for the delivery of TGFβ3 and with or without an alternate fiber population, poly(caprolactone) (PCL). After 12 weeks in vivo, it was observed that material choice and the inclusion of TGFβ3 had the most significant impact on outcomes; specifically, PCL scaffolds without TGFβ3 had increased bone remodeling and decreased macroscopic appearance and mechanical properties, whereas MeHA and both TGFβ3-releasing scaffolds had improved histological scores and type 2 collagen content. To further improve potential utility of such a system, studies were also undertaken to include the cell-recruiting cytokine stromal derived factor 1-α (SDF-1) along with TGFβ3 for improved repair. Controlled, specific release of SDF-1 was achieved through incorporation of sulfated HA macromers, and future work includes investigation of SDF-1-releasing fibrous HA hydrogels in vivo. Ultimately, the investigation of these fibrous HA hydrogels provided insight towards biomaterial design for cartilage tissue engineering.
Marklein, Iris K., "Engineered Fibrous Hyaluronic Acid Hydrogels for Cartilage Repair" (2014). Publicly Accessible Penn Dissertations. 1359.